In general, tumor antigens cannot be efficiently presented by an antigen presenting cell, that is, immune response is not effectively induced. An antitumor vaccine is a novel therapeutic vaccine which is characterized by activating tumor specific immune system (for example, introducing tumor antigens to antigen presenting cells) to induce a strong immune response to destroy cancer cells.
Of the available vaccine approaches, cellular vaccines using antigen presenting cells (APC) such as dendritic cells (DC) are known to be reliable at generating effective T cell immunity (Rosenberg, S. A. et al., Nat. Med., 10, 909-915, 2004). Because DC-based vaccines in particular have been shown to efficiently induce Ag-specific effector and memory T cells, they are being considered for antitumor immunotherapy in a number of clinical trials (Rosenberg, S. A. et al., Nat. Med., 10, 909-915, 2004). Dendritic cells are ideal antigen-presenting cells (APC) for immunotherapy because they can capture Ag and then migrate into lymphoid organs, where they present the Ag to the relevant T cell. More importantly, they provide strong co-stimulation to the T cells (Figdor, C. G. et al., Nat. Med., 10, 475-480, 2004; and Banchereau, J. et al., Cell, 106, 271-274, 2001). The DC-vaccine approach is well-established for both experimental and clinical studies. However, DCs are relatively sparse in blood and lymphoid tissues and it is difficult to increase their numbers ex vivo from blood monocytes, both of which present major drawbacks to their widespread use in vaccines (Schultze, J. L. et al., Trends Immunol., 25, 659-664, 2004).
B cells offer an attractive alternate source for cellular vaccines in that they are abundant in lymphoid tissues and blood, and easily expanded ex vivo (Schultze, J. L. et al., Trends Immunol., 25, 659-664, 2004; von Bergwelt-Baildon, M. S. et al., Blood, 99, 3319-3325, 2002; and Schultze, J. L. et al., J. Clin. Invest., 100, 2757-2757, 1997), and home to lymphoid organs after parenteral administration.
Despite these advantages, B cells have been ignored as a source of the cellular vaccine since they are poorly immunogenic. In fact, accumulating evidence shows that they induce immune tolerance in both CD4 and CD8 T cells directly, probably due to the lack of co-stimulation (Bennett, S. R. et al., J. Exp. Med., 188, 1977-1983, 1998; and Eynon, E. E. et al., J. Exp. Med., 175, 131-138, 1992). However, ‘activated’. B cells can prime both CD4 and CD8 T cells (von Bergwelt-Baildon, M. S. et al., Blood, 99, 3319-3325, 2002; Schultze, J. L. et al., J. Clin. Invest., 100, 2757-2765, 1997; Lapointe, R. et al., Cancer Res., 63, 2836-2843, 2003; and Heit, A. et al., J. Immunol., 172, 1501-1507, 2004), suggesting that, when activated by the appropriate stimuli, B cells can act as immunogenic APC capable of inducing Ag-specific T cell immunity.
It is well established that iNKT cells play a crucial role in a variety of immune responses and in immunopathology as a whole. Although they represent less than 1% of lymphocytes in mice, iNKT cells govern the response to self- and exogenous-Ag and determine whether tolerance or immunity is induced (Kronenberg, M., Annu. Rev. Immunol., 23, 877-900, 2005; and Park, S. H. & Bendelac, A., Nature, 406, 788-792, 2000). They act as suppressors of immunity in tumor, diabetes and at immune-privileged site (Sonoda, K. H., et al., J. Exp. Med., 190, 1215-1226, 1999).
In contrast, ligand-mediated activation of iNKT cells lead to the activation of T, B, and NK cells as well as DC. Injection of αGalCer, an iNKT ligand, generates antitumor immunity via the mediation of NK and T cells (Moodycliffe, A. M., et al., Nat. Immunol., 1, 521-525, 2000).
Alpha-galactosylceramide (αGalCer) is a kind of glycolipid extracted from marine sponge, which is the ligand of natural killer T cell having Vα14+ T cell receptor (TCR) and presented by CD1d on an antigen presenting cell (APC) (Kawano et al., Science, 278: 1626, 1997). The activation of the natural killer T cells leads to the mass-production of IFN-γ and IL-4, by which immune responses against either infectious disease or cancer can be controlled (Chen et al., J. Immunol., 159: 2240, 1997; Wilson et al., Proc. Natl. Acad. Sci. U.S.A., 100: 10913, 2003).
Mice to which protein Ag and αGalCer have been coadministered develop humoral and cell-mediated immunity including cytotoxic T cell responses (Hermans, I. F., et al., J. Immunol, 171, 5140-5147, 2003; and Stober, D. et al., J. Immunol., 170, 2540-2548, 2003). Furthermore, a recent study has demonstrated that αGalCer-loaded DC generate longer-lasting iNKT cell responses than does free-form of αGalCer, suggesting that the adjuvancity of iNKT-ligands could be enhanced by targeting it to professional APC.
The present inventors confirmed that presentation of the iNKT-ligand on B cells could convert them from tolerogenic to immunogenic, thereby generating strong immunity against Ag displayed on MHC molecules of the B cells. To verify the confirmation and thereby to complete this invention, the present inventors further confirmed the efficiency of αGalCer-loaded, peptide-pulsed B cells and αGalCer-loaded, adenovirus-transduced B cells in generating antigen specific immunity and anti-tumor activity.